AB0125 IL-25 PARTICIPATES IN KERATINOCYTE-DRIVEN DERMAL MATRIX TURNOVER AND IS REDUCED IN SYSTEMIC SCLEROSIS (SSc) EPIDERMIS
Authors: B. Russo, J. Borowczyk, P. Cacialli, P. Moguelet, M. E. Truchetet, A. Modaressi, N. Brembilla, J. Bertrand, W. H. Boehncke, C. Chizzolini
Journal: Annals of the Rheumatic Diseases (2022)

Background Evidence shows that dysfunctional SSc keratinocytes contribute to fibrosis by altering dermal homeostasis (1, 2). Whether interleukin-25 (IL-25), an IL-17 family member regulating many epidermal functions (3), takes part in skin fibrosis is unknown. Objectives To investigate the role of IL-25 in skin fibrosis. Methods The expression of IL-25 was evaluated by immunofluorescence and in situ hybridization in 10 SSc and 7 healthy donors (HD) skin biopsies. Epidermal equivalents (EE) reconstituted by primary HD keratinocytes were used as a model to study transcriptomic changes induced by IL-25 in the epidermis. RNA expression profile in EE was characterized by RNAseq. The conditioned medium (CM) from primary SSc and HD keratinocytes primed with IL-25 was used to stimulate fibroblasts. IL-6, IL-8, MMP-1, type-I collagen (col-I), and fibronectin production by fibroblasts was assessed by ELISA. Results SSc epidermis expressed lower levels of IL-25 compared to HD. In EE, IL-25 regulated several molecular pathways related to wound healing and extracellular matrix (ECM) remodeling. Compared to control CM, the CM from IL-25-primed keratinocytes enhanced the fibroblast production of MMP-1, IL-6, IL-8, but not of Col-I nor fibronectin. However, IL-25 significantly reduced the production of Col-I when applied directly to fibroblasts and partially inhibit α-smooth muscle actin (α-SMA) expression promoted by TGFβ. The activation of keratinocytes by IL-25 was receptor-dependent and evident after a very short incubation time (10 min), largely mediated by IL-1, suggesting enhanced and specific release of preformed mediators. Conclusion These results show that IL-25 participates to skin homeostasis and its decreased expression in SSc may contribute to skin fibrosis by favoring ECM deposition over degradation. References [1]Russo B, Brembilla NC, Chizzolini C. Interplay between Keratinocytes and Fibroblasts: A Systematic Review Providing a New Angle for Understanding Skin Fibrotic Disorders. Frontiers in immunology. 2020; 11:648. [2]Russo B, Borowczyk J, Boehncke WH, Truchetet ME, Modarressi A, Brembilla NC, et al. Dysfunctional keratinocytes increase dermal inflammation in systemic sclerosis. Results from tissue-engineered scleroderma epidermis. Arthritis &amp; rheumatology. 2021. [3]Borowczyk J, Shutova M, Brembilla NC, Boehncke WH. IL-25 (IL-17E) in epithelial immunology and pathophysiology. J Allergy Clin Immunol. 2021. Acknowledgements We thank Natacha Civic and Mylène Docquier (Genomics Platform) for performing the RNA sequencing; Nicolas Laudet (Bioimaging Core Facility) for quantification of immune-histology, François Prodon and Olivier Brun for microscope imaging (Bioimaging Core Facility), Marie Ebrahim Malek and Laura de Luca (Histology Core Facility) for contribution to tissue preparation (all at University Medical Center, Geneva, Switzerland). Disclosure of Interests Barbara Russo: None declared, Julia Borowczyk: None declared, Pietro Cacialli: None declared, Philippe Moguelet: None declared, Marie-Elise Truchetet Speakers bureau: Abbvie, Lilly, SOBI and Boehringer Ingelheim, Ali Modaressi: None declared, Nicolò Brembilla: None declared, Julian Bertrand: None declared, Wolf-Henning Boehncke Speakers bureau: Abbvie, Almirall, BMS, Celgene, Leo, Lilly, Novartis, and UCB, Carlo Chizzolini Speakers bureau: GSK, Roche, Boehringer Ingelheim